Novel mechanisms refer to drugs that work in new ways. Often these agents are part of a new class, and they have the potential to provide new treatment options for multiple myeloma.
There are a number of emerging classes of drugs targeting specific defects within cells that are associated with the development and progression of multiple myeloma. These new agents are typically combined with proteasome inhibitors and/or immunomodulatory drugs (IMiDs®, Celgene) and could potentially benefit a broad range of patients.
In 2015, the FDA approved the first histone deacetylase (HDAC) inhibitor under the name Farydak® (panobinostat, Novartis). It is for patients whose disease has relapsed and no longer responds to the proteasome inhibitor Velcade (bortezomib, Takeda Oncology), one of the most effective treatments for multiple myeloma.
Just as proteasome inhibitors work by blocking the function of the proteasome pathway, Farydak blocks the aggresome pathway. When given with a proteasome inhibitor like Velcade, both pathways are blocked, preventing cells—especially cancer cells—from disposing of proteins. This combined action slows down cancer growth, ultimately killing the cancer cells.
Bromodomain inhibitors work by targeting a bromodomain-containing protein called BRD4. This protein serves to increase the expression of genes that promote cancer cell proliferation and survival. Targeting these proteins can be a way to turn them off, arresting the growth of cancer cells.
The first Phase 1 clinical trial of a bromodomain inhibitor called TEN 010 (Tensha Therapeutics) is in its early stages. Researchers believe that this approach has promise for multiple myeloma.
Filanesib (ARRY-520, Array BioPharma) is a member of a class of drugs known as kinesin spindle protein (KSP) inhibitors. Filanesib works by disrupting cell division. Numerous clinical trials have been completed pointing to its effectiveness in patients who have had between six and eight previous treatments and whose myeloma no longer responds to Velcade.
In particular, filanesib has shown promise when used alone or with a steroid. During Phase 1 trials, it has been less effective than expected when used in combination with one of the newer proteasome inhibitors such as Kryprolis® (carfilzomib, Onyx Pharmaceuticals, an Amgen subsidiary). A Phase 2, Multiple Myeloma Research Consortium (MMRC) clinical trial testing this combination is currently underway. Another issue that may affect filanesib’s future use is that it tends to suppress white blood counts, making it harder for patients to fight infections.
Clinical trials have also revealed that alpha 1-acid glycoprotein (AAG), a protein found in the blood, may be a predictor for patients’ response to filanesib. Those patients with low levels of AAG tend to respond better than those with high levels of AAG. This information may serve as a way to screen appropriate candidates for treatment with filanesib.
Another class of drugs being investigated in myeloma is called selective inhibitor of nuclear export, or SINE. One drug in this class, selinexor (KPT-330, Karyopharm Therapeutics), is currently in clinical trials. One of those studies, a Phase 2, MMRC clinical trial, has just started. It is testing selinexor in combination with low-dose dexamethasone in heavily-treated patients whose myeloma no longer responds to Velcade, Revlimid® (lenalidomide, Celgene), Kyprolis, and Pomalyst® (pomalidomide, Celgene).
The SINE class of drugs works by inhibiting the nuclear export protein XPO1 (also called CRM1). As a result, tumor suppressor proteins accumulate in the cell nucleus, which amplifies their ability to stop tumor growth. Researchers suspect that this action leads to the death of cancer cells. An added benefit of this treatment is that it appears to leave normal cells intact.
In a small clinical trial, selinexor has proved to be effective in patients who have had numerous treatments for multiple myeloma. When paired with dexamethasone, nausea is reduced significantly. Furthermore, selinexor is even more effective when paired with dexamethasone and Kyprolis. Though still early in the clinical trial phase, these pairings show considerable promise.